The measurement of internal body conditions through external measurements defines the art of medical diagnostics. It is a goal of medical diagnostic devices to be as minimally invasive as possible to achieve measurement of internal processes. Consequently, many devices have been designed which permit the measurement of bodily functions through electrical or electrochemical skin surface measurements.
The measurement of blood glucose levels in diabetic patients is essential to the proper management and treatment of the disease. The proper modulation of blood glucose by the administration of insulin, insulin analogs or oral hypoglycemic agents requires that multiple samples of blood be taken throughout each day. Existing diagnostic systems for the measurement of blood glucose are primarily based on the removal of a small sample of blood from the individual which is analyzed in a specialized device to determine and correlate blood glucose. As there may be considerable discomfort involved in obtaining the blood sample, patient compliance with treatment regimens is affected and effective treatment of the disease is impeded.
Consequently, multiple approaches have been examined to produce a relatively painless "non-invasive" glucose monitoring device. One approach has been to measure glucose levels in sweat which may be correlated to serum blood glucose. However, the concentrations of glucose in such samples is so low and fluctuates with environmental conditions that accurate correlation with blood glucose is difficult. However, the non-invasive aspects of this mode of measurement are sufficiently attractive to invite further study.
The concentration of glucose in a sample may be quantified electrochemically. Although glucose itself will not react selectively at a catalytic electrode surface to produce a measurable electrical effect, a cascade mechanism involving the enzyme glucose oxidase produces hydrogen peroxide which will react at an electrode surface to produce a measurable electrical current proportional to glucose concentration. Devices for the measurement of electrochemically significant quantities of analytes, such as glucose, extracted through the skin require electrodes of sufficient size and sensitivity to accommodate the extremely low concentration of glucose obtainable. Design of such electrodes is complicated by the inherent "noise" of the surrounding environment and the inherent electrical properties of the materials involved in producing such a device.
In an effort to increase the quantity of glucose obtained through the surface of the skin and to provide reproducibility in the quantity of fluid extracted through the skin surface, a glucose monitoring system has been proposed which is based on the active extraction of glucose through the surface of the skin by the process of "reverse iontophoresis." Reverse-iontophoresis is a process by which compounds are extracted through the surface of the skin by the application of an electrical field. Although charged species would be expected to move under the influence of the electric field, it has been found that uncharged species (such as glucose at physiological pH) will also co-migrate with the charged species. It has been determined that the quantity of glucose obtained by such methodology does correlate reproducibly to serum blood glucose measurements. Tamada, et al. (1995) Nature Medicine 1:1 198-1201. However, the quantity of glucose obtainable by such methodology remains substantially lower than the concentration of glucose in raw blood samples. Glucose is present in whole blood in a concentration of approximately 5 millimolar. In comparison, the concentration of glucose in fluid obtained as described in the system above is on the order of 2 micromolar to 100 micromolar. Consequently, conventional electrochemical systems for the measurement of blood glucose are not suitable for measurement of blood glucose in such concentrations.
Efforts to increase the quantity of glucose extracted have been described. Primarily, these methods have focused on increasing the permeability of the skin. Traditional chemical permeation enhancers such as PGML, (propylene glycol monolaurate) have been employed. Other methods known to increase skin permeability such as electroporation and ultrasound have also been employed. A device for the transcutaneous measurement of glucose having a two-chamber system is described in U.S. Pat. No. 5,362,307, issued Nov. 8, 1994 and U.S. Pat. No. 5,279,543, issued Jan. 18, 1994 the entire teachings of which are herein incorporated by reference. A modification to this system has been devised in which the polarity of the two electrodes is periodically reversed resulting in enhanced extraction of glucose through the skin. (Tamada, et al. ibid.) The quantity of glucose obtained using the alternating polarity protocol enables a sufficient quantity of glucose to be extracted to be electrochemically measured. However, in order to enable the device to operate in the alternating polarity mode, each chamber must contain both a set of sensing electrodes and an iontophoretic electrode. The inclusion of both sensor and iontophoretic electrodes in each chamber limits the size of each electrode based on spatial limitations. Furthermore, the inclusion of both iontophoretic and sensing electrodes in each chamber adds to the complexity and cost of the device.